This application is directed to the fields of bioinformatics and inflammatory and autoimmune diseases, with Juvenile Idiopathic Arthritis (JIA) as an example of these diseases. The present teachings relate to methods and compositions for assessing, diagnosing, monitoring, assessing disease and flare activity, and selecting treatment for inflammatory disease and autoimmune disease; e.g., JIA.
JIA is the most common rheumatic disease affecting children and adolescents. The annual incidence rate of pediatric rheumatic diseases is estimated to be 1 per 1,000 children, with an estimated prevalence of 50,000 to 70,000 children with JIA in the United States (Harrold et al., J. Rheumatology 40:1218-1225 (2013); Helmick et al., Arthritis and rheumatism 58:15-25 (2008); Weiss and Ilowite, Juvenile idiopathic arthritis 52:413-42 (2005)). JIA encompasses seven categories of disease, which include oligoarticular JIA (50-60% of cases), polyarticular rheumatoid factor (RF) positive JIA (5-10%), polyarticular RF negative JIA (30-50%), systemic JIA (10-20%), psoriatic JIA (2-15%), enthesitis-related arthritis (1-7%), and undifferentiated arthritis (5-10%) (Duffy et al., Arthritis and rheumatism 52:382-5 (2005); Weiss (2005)). Presentation, severity, and course of disease vary widely, from a benign self-limiting course, to severe, unremitting disease resulting in progressive joint destruction, skeletal deformity, growth retardation, possible blindness, and long-term disability (Packham and Hall, Rheumatology 41:1428-1435 (2002)).
Recent advances have expanded the treatment options available for treatment of JIA (Ruth and Passo, Therapeutic Advances in Musculoskeletal Disease 4:99-110 (2005)). Biologic agents targeting TNF, interleukin (IL)-1 receptor, and T-cell co-stimulation receptors are approved for JIA (Packman and Hall (2002)). Treatment goals for childhood arthritis are thus becoming more aggressive, with remission of the disease as the expectation. However, remission rates differ in frequency and durability between JIA categories even with the use of biologic treatments (Adib et al., Rheumatology 44:995-1001 (2005); Hyrich et al., Rheumatology 49: 116-22 (2010)).
Current therapeutic approaches to JIA are hindered by lack of good outcome measures. Despite substantial efforts, no validated, continuous measure of disease activity has been identified that clinicians can use to monitor disease status in individual patients, develop standards of care, assess quality of care, or use as a clinical trial end point (Wallace et al., Arthritis care & research 63: 929-36 (2011)). The 1997 American College of Rheumatology pediatric improvement criteria (ACR Pediatric 30) established a core set of outcome values for clinical trials (Giannini et al., Arthritis and rheumatism 40:1202-1209 (1997)) that include physician global assessment of disease activity (MD global), parent/child global assessment of well-being (PGA), functional ability (also known as CHAQ, Child/Parent Health Assessment Questionnaire), active arthritic joint counts and Westergren erythrocyte sedimentation rate (ESR). However, the ACR Pediatric 30 measures the degree of improvement from baseline and its use is limited to clinical trials for measuring minimal therapeutic efficacy for new medications. The more recently developed Juvenile Arthritis Disease Activity Score (JADAS) is a composite tool that includes four core variables of the ACR Pediatric 30: MD global, PGA, active joint counts, and ESR (Consolaro et al., Arthritis and rheumatism 61: 658-66 (2009)). Additional JADAS versions have been proposed, including a version that uses the C-reactive protein (CRP) in place of the ESR and one that does not include any measure of inflammation (Nordal et al., Annals rheumatic disease 71: 1122-7 (2012)). Both the JADAS and composite disease activity measures developed for adult RA (e.g., Disease Activity Score (DAS), DAS28, Clincial Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI)) have shown validity as measures for JIA disease state (Ringold et al., Arthritis care & research 62:1095-102 (2010)); Consolaro et al., Arthritis and rheumatism 61:658-66 (2009)). However, while the JADAS and RA composite measures hold promise for use in routine pediatric practice, these measures may misclassify active disease as inactive (Ringold (2010)). Furthermore, discordance has been reported between various core measures (MD global, PGA, and CHAQ) used to assess disease activity and functional ability in JIA patients (Consolaro et al., J. Rheumatology 34: 1773-76 (2007); Ravelli (2001); Giannini et al., Arthritis and rheumatism 40: 1202-1209 (1997)).
Accurate, ongoing evaluation of disease activity is critical for optimally managing JIA, to minimize the joint damage and long-term functional disability that can result from persistent active disease. To achieve the maximum therapeutic benefits for individual subjects, it is important to be able to specifically quantify and assess the subject's disease activity at any particular time, determine the effects of treatment on disease activity, and predict future outcomes. No existing single biomarker or multi-biomarker test produces results demonstrating a high association with level of HA disease activity. The embodiments of the present teachings identify multiple serum biomarkers for the accurate clinical assessment of disease activity in subjects with chronic inflammatory disease, such as JIA, along with methods of their use.